7-(Substituted)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamines

ABSTRACT

7-(Substituted)-pyrrolo[3,2-f]-quinazoline-1,3-diamines possess antibacterial activity in vitro. The invention also provides compounds having synergism in vivo with sulfa drugs against bacterial infections.

Various derivatives of 2,4-diaminoquinazoline and2,4,6-triaminoquinazoline are described in the literature and are knownto possess antifolic activity in bacterial systems. Such compounds arealso known to exhibit antibacterial or antiprotozoal activity. Forexample, 2,4-diaminoquinazolines having an alkyl group at the 5-positionand/or 6-position or having a trimethylene bridge between the 5- and6-position possess antibacterial activity [see Hitchings et al., U.S.Pat. No. 2,945,859 or De Graw et al., J. Med. Chem., 17, 762 (1974)].2,4-Diamino-6-[(arylmethyl)amino]-quinazolines;2,4-diamino-6-{[(substituted aryl)methyl]amino}-quinazolines; and2,4-diamino-6-{[(heterocyclic)methyl]amino}-quinazolines along withderivatives having a 5-alkyl substituent or N⁶ -alkyl substituentexhibit antimalarial activity. [See Davoll et al., J. Med. Chem., 15,812 (1972); Elslager et al., J. Med. Chem., 15, 1138 (1972); see alsothe review article by E. Elslager entitled, "New Perspectives on theChemotherapy of Malaria, Filariasis, and Leprosy," Progress in DrugResearch 18, 99- 172 (1974), in particular pages 111-116 and 152-154].

The pyrrolo[3,2-f]quinazoline-1,3-diamines of the invention differ fromthe known 2,4,6-triaminoquinazolines in that the 5-position and the N⁶position of the latter are bridged by an ethylene moiety thus forming anovel tricyclic heterocycle.

The invention sought to be patented comprises compounds of the formula:##STR1## or a non-toxic acid addition salt thereof, wherein: Y is --CH₂R or --R¹

wherein:

R is 2,4-dichlorophenyl, 3-acetylphenyl, 3-carbomethoxyphenyl,3-isopropylphenyl, 4-carboisopropyloxyphenyl, 4-carbo-2-pentyloxyphenyl,4-carbomethoxyphenyl, or 4-hydroxyphenyl;

and

R¹ is 4-pyridinyl, 2-(4-methylpyridinyl), 4-trifluoromethylphenyl, or4-carbamoylphenyl.

The compounds of Formula I, wherein Y, R, and R¹ are as hereinbeforedefined or the salts thereof, inhibit the growth of bacteria in vitro asdemonstrated in a standard tube dilution test employing seed agar orWellcotest Sensitivity Test Agar fortified with 5% hemolyzed horse bloodas the growth medium. The compounds have shown activity in vitro againstone or more of the following strains of bacteria: S. aureus Smith, S.aureus 53-180, N. catarrhalis 8193, E. coli 9637, S. paratyphi 11737, K.pneumoniae 10031, or P. vulgaris 6896.

The invention also provides compounds which will potentiate theantibacterial effects of sulfa drugs. When tested by the oral route ofadministration in mice,7-(4-pyridinyl)-7H-pyrrolo[3,2-f]-quinazoline-1,3-diamine gave asynergistic effect with sulfamethoxazole against bacterial infections.

In general, the compounds of Formula I having an N⁷ -substituent areprepared by reacting 7-H-pyrrolo[3,2-f]quinazoline-1,3-diamine with analkali metal base to form the corresponding alkali metal salt, and thesalt is reacted with the appropriate reagent, RCH₂ --Z or R¹ --Z, inorder to attach the desired substituent, RCH₂ -- or R¹ --, at the7-position. The base employed in the first step must be of sufficientstrength to remove the proton from the indolic nitrogen of the startingmaterial. Examples of such bases are sodium and potassium hydride,potassium t-butoxide, and lithium or potassium amide.

In the reagents RCH₂ --Z or R¹ --Z, R and R¹ are as defined hereinbeforewith respect to Formula I (except that R and R¹ cannot be a group whichcontains a free hydroxyl group as a substituent) and Z is a leavinggroup.

When the reagent is RCH₂ --Z, the preferred leaving group Z is achlorine, bromine, or iodine atom. When the reagent is R¹ --Z, thepreferred leaving group is a fluorine, bromine, chlorine, or iodineatom. Other examples, of appropriate leaving groups (Z) for RCH₂ --Z aretosyloxy or mesyloxy. The reaction is conveniently carried out in aninert solvent, such as dimethylformamide (DMF) or dimethylacetamide(DMA). In a preferred method, the7-H-pyrrolo[3,2-f]quinazoline-1,3-diamine is treated with sodium-hydridein dimethylformamide and the appropriate reagent (RCH₂ --Z or R¹ --Z) isadded to the reaction mixture. In the reaction employing the reagent R¹--Z, it is preferred to heat the reaction mixture at a temperature above50° C.

7-H-Pyrrolo[3,2-f]quinazoline -1,3-diamine is prepared by heating anacid addition salt of 5-aminoindole at a temperature of about 185°-215°C. with an alkali metal dicyanamide, such as sodium or potassiumdicyanamide, in an aliphatic alcohol solvent. Best results are achievedif a >2:1 molar ratio of the dicyanamide to the 5-aminoindole acidaddition salt is employed. A molar ratio of about 2.5:1 is preferred.The reaction is conveniently carried out by heating the reactants at thereflux temperature of the solvent. Aliphatic alcohols having a boilingpoint of about 185° C. to about 215° C. are preferred solvents. In apreferred method, the 5-aminoindole acid addition salt is heated atreflux temperature in 1-octyl alcohol with sodium dicyanamide until thereaction is complete.

When it is desired to prepare a compound of Formula I wherein --CH₂ --Ror R¹ contain a free aromatic hydroxy group, such compound can beconveniently prepared by cleavage of a corresponding aromatic methoxycompound. For example,7-[(4-hydroxyphenyl)methyl]-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine isprepared by cleaving7-[(4-methoxyphenyl)methyl]-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine inthe presence of boron tribromide.

The starting materials which are 5-aminoindole and the reagents RCH₂ --Zand R¹ --Z are either known compounds or can be prepared by knownmethods for analogous compounds or by obvious modifications of the knownmethods.

The compounds of Formula I may be isolated and purified either in theform of the free bases or the acid addition salts. Methods forconverting one such form to another will be obvious to one skilled inthe art of chemistry.

For pharmacological use, the compounds of Formula I may be administeredin the form of an acid addition salt of a non-toxic organic or inorganicacid. The salts may be prepared by methods well known in the art.Appropriate salts are those formed from the following acids:hydrochloric, hydrobromic, maleic, benzoic, pamoic, methanesulfonic, oracetic.

For pharmacological use, the compounds of Formula I may be administeredalone or in combination with pharmaceutically acceptable carriers, theproportion and nature of which are determined by the solubility andchemical properties of the compound selected, the chosen route ofadministration, and standard pharmaceutical practice. For example, thecompounds of Formula I may be administered orally in solid dosage forms,e.g. capsules, tablets, or powders, or in liquid forms, e.g. solutionsor suspensions. The compounds may also be injected parenterally in theform of sterile solutions or suspensions. Solid oral forms may containconventional excipients, for instance: lactose, succrose, magnesiumstearate, resins, and like materials. Liquid oral forms may containvarious flavoring, coloring, preserving, stabilizing, solubilizing orsuspending agents. Parenteral preparations are sterile aqueous ornon-aqueous solutions or suspensions which may contain variouspreserving, stabilizing, buffering, solubilizing, or suspending agents.If desired, additives, such as saline or glucose may be added to makethe solutions isotonic.

The following examples are illustrative of the methods of making andusing the compounds of the invention. All temperatures are incentigrade.

EXAMPLE 1 7-H-Pyrrolo[3,2-f]quinazoline-1,3-diamine

A suspension of 168.6 g. 5-aminoindole hydrochloride (prepared bytreating a methanolic suspension of 5-aminoindole with excessisopropanolic hydrogen chloride and diluting the salt solution withether), 222 g. sodium dicyanamide (previously recrystallized frommethanol), and 3 l. 1-octanol are refluxed with thorough stirring (undernitrogen) for 13 hours, and the hot mixture is filtered. The insolublesare washed with 500 ml. hot 1-octanol; the combined filtrates arediluted with an equal volume of ether and are acidified to pH 1 withisopropanolic hydrogen chloride. A fine, yellow precipitate is collectedby filtration (slow) and is dissolved in 3 l. warm water. The aqueoussolution is filtered through a coarse, sintered glass funnel. Uponcooling to ca. 25° C., the solution is washed with ethyl acetate andwith ether. Basification of the solution with aqueous sodium hydroxideaffords a yellow precipitate which is collected, thoroughly washed withwater and dried to constant weight. The crude product (141.5 g.) isdissolved in ca. 10 l. methanol, treated with charcoal, and filteredthru Celite. The methanolic solution is concentrated to a volume of ca.400 ml., diluted with 200 ml. acetone and chilled.

The solid that separates is washed with cold acetone and is dried toprovide 77.6 g. of the title compound, m.p. 263°-265° (dec.). Anadditional 17.2 g. of product [m.p. 262°-264° (dec.)] are isolated byconcentrating the crystallization mother liquor to a volume of ca. 40ml., adding 40 ml. acetone, and chilling. Recrystallization of a 1.0 g.quantity of product [m.p. 263°-265° (dec.)] from methanol-acetone gives395 mg. title compound, m.p. 264° (dec.); NMR (dDMSO): δ 7.14 (doublet,J=3 Hz, 9H), 7.20 (doublet, J=9 Hz, 5 or 6H), 7.54 (doublet, J=3 Hz,8H), 7.78 (doublet, J=9 Hz, 5 or 6H), 11.65 (broad singlet,exchangeable, 7H) p.p.m.; λ_(max) ^(95%) EtOH 232.5 (ε 24,300), 258 (ε22,120), 312 (ε 8,090), 340.5 (ε 7,420) nm; λ_(min) ^(95%) EtOH 250 (ε20,940), 279 (ε 2,310), 330 (ε 7,140) nm.

7-H-Pyrrolo[3,2-f]quinazoline-1,3-diamine (5.62 g. prepared in a mannersimilar to that described above) in 300 ml. methanol is treated withexcess isopropanolic hydrogen chloride, and the solution is concentratedto a volume of ca. 100 ml., diluted with 200 ml. dimethoxyethane, andthoroughly cooled. The salt is collected and dried. Weight 2.7 g.Concentration of the mother liquor provides an additional 3.8 g. salt.Recrystallization of the two solids from methanol-ethanol yields 5.26 g.title compound as the monohydrochloride salt m.p. >310°.

Analysis for: C₁₀ H₉ N₅.HCl; Calculated: C, 50.96; H, 4.28; N, 29.72;Cl, 15.05; Found: C, 50.81; H, 4.22; N, 30.01; Cl, 14.88.

Employing conditions similar to those above, A. Rosowsky and N.Papathanasopoulos [J. Org. Chem., 39, 3293 (1974)] convertednaphthylamines into 2,4-diaminobenzo[h]quinazolines.

EXAMPLE 27-[(2,4-Dichlorophenyl)methyl]-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine

A suspension of 7.97 g. of 7-H-pyrrolo[3,2-f]quinazoline-1,3-diamine in500 ml. of dry dimethylformamide is stirred under nitrogen as 4.61 g. ofca. 50% sodium hydride-mineral oil dispersion is added carefully. Afterstirring for 1.5 hours, a solution of 8.99 g. of 2,4-dichlorobenzylchloride in 30 ml. of dry dimethylformamide is added during ca. 10minutes. Stirring is continued for 5 hours and then 25 ml. of glacialacetic acid is added to the reaction mixture. After removal of solvent(in vacuo), the residue is stirred throughly with a mixture of excessaqueous potassium carbonate solution and 100 ml. of 1 N sodium hydroxidesolution and filtered. The crude product is dissolved in 5 liters ofboiling methanol, treated with charcoal, and filtered through Celite.The filtrate is concentrated to ca. 500 ml. and chilled. The crystallinesolid is collected and again recrystallized from methanol to afford 6.33g. of the title compound, m.p. 249°-250° C., NMR (dDMSO and D₂ O): δ5.58 (singlet, N--CH₂ --C₆ H₃ Cl₂), 6.68 (doublet, J=8 Hz, 5H), 7.10(doublet, J=3 Hz, 9H), 7.52 (doublet, J=3 Hz, 8H), 7.68 (doublet, J=8Hz, 6H) p.p.m.; λ_(max) ^(95%) EtOH 258 mμ (26,000) and 315 mμ (8,500).

Analysis for: C₁₇ H₁₃ N₅ Cl₂ ; Calculated: C, 57.00; H, 3.66; N, 19.55;Cl, 19.80; Found: C, 56.97; H, 3.75; N, 19.63; Cl, 18.85.

EXAMPLES 3-8

Employing conditions similar to those recorded in Example 2,7H-pyrrolo[3,2-f]quinazoline-1,3-diamine, in dimethylformamide, isconverted to the Nind-sodium salt with ca. 50% sodium hydride-mineraloil dispersion and the salt is reacted with the indicated halide for thespecified period to provide the7-(substituted)methyl-7-H-pyrrolo[3,2-f]quinazoline-1,3-diaminesdescribed in Table I.

                                      TABLE I                                     __________________________________________________________________________    7-(Substituted)-7-H-pyrrolo[3,2-f]quinazoline-1,3-diamines                     ##STR2##                                                                     Example                    Reax. Time                                                                          Recryst.                                     No.    R        Alkylating Agent                                                                         (hours)                                                                             Solv.     m.p., °C.                   __________________________________________________________________________    3    3-acetylphenyl                                                                           3-acetylbenzyl                                                                           5     dimethylformamide                                                                       279-281 (dec.)                                     bromide.sup.a                                                 4    3-carbomethoxyphenyl                                                                     3-carbomethoxybenzyl                                                                     16    dimethylformamide                                                                       261.5-264                                          bromide.sup.b                                                 5    3-isopropylphenyl                                                                        3-isopropylbenzyl                                                                        21    methanol  213-215                                            bromide.sup.a                                                 6    4-carboisopropyloxy-                                                                     4-carboisopropyloxy-                                                                     18    isopropanol                                                                             236-240                                 phenyl     benzyl bromide.sup.b                                          7    4-carbo-2-pentyloxy-                                                                     4-carbo-2-pentyloxy-                                                                     16    dimethylformamide                                                                       233-235                                 phenyl     benzyl bromide.sup.b                                          8    4-carbomethoxyphenyl                                                                     4-carbomethoxybenzyl                                                                     5.5   dimethylformamide                                                                       232-235                                            bromide.sup.b                                                 __________________________________________________________________________     .sup.a This bromide is prepared from the corresponding methyl ether by        treatment with hydrogen bromide                                               .sup.b This ester is prepared for the corresponding acyl bromide by           treatment with the appropriate alcohol.                                  

EXAMPLE 97-[(4-Hydroxyphenyl)methyl]-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine

Treat a suspension of 3.2 g. of7-[(4-methoxyphenyl)-methyl]-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in100 ml of methylene chloride at -5° C. with 34 ml. of 0.92 M borontribromide in methylene chloride. Keep the reaction at 20° C. for 18hours and dilute with 100 ml. of water. Filter the resultingprecipitate, stir in an aqueous potassium carbonate solution, filter,wash with water and dry. Crystallize the precipitate twice from methanoland once from dimethylformamide to obtain 0.63 g. of the title product,m.p. 292° C. (dec.), NMR (dDMSO): δ 5.33 (singlet, N--CH₂ --C₆ H₅ O),6.67 (doublet, J=9 Hz, 5H), 6.72 (doublet, J=3 Hz, 9H), 7.51 (doublet,J=3 Hz, 8H), 7.75 (doublet, J=9 Hz, 6H) p.p.m.

Analysis for: C₁₇ H₁₅ N₅ O.1/2 dimethylformamide; Calculated: C, 64.99;H, 5.46; N, 22.53; Found: C, 64.98; H, 5.33; N, 22.51.

EXAMPLE 10 7-(4-Pyridinyl)-7H-pyrrolo-[3,2-f]quinazoline-1,3-diamine

A solution of 7.97 g. of 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine in 500ml. of dry dimethylformamide is stirred, under nitrogen, with 4.61 g.ca. 50% sodium hydride-mineral oil dispersion for 1.5 hours. Addition of8.95 g. of p-bromopyridine hydrochloride is followed by heating of thereaction mixture at 110° C. for 5 hours. Glacial acetic acid (10 ml) isadded and the solvent is removed in vacuo. The residue is stirredthoroughly with a mixture of excess aqueous potassium carbonate solutionand 100 ml. of 1 N sodium hydroxide solution, collected, washed withwater and dried. Three crystallizations from methanol and one fromdimethylformamide and drying afford 0.61 g. of the title product, m.p.328.5°-329.5° C., NMR (dDMSO): δ 7.16 (doublet, J=8 Hz, 5H), 7.22(doublet, J=3 Hz, 9H), 7.88 (doublet, J=3 Hz, 8H), 7.96 (doublet, J=8cps, 6H), p.p.m. λ_(max) ^(95%) EtOH 255 mμ (22,900) and 297 mμ(22,100).

Analysis for: C₁₅ H₁₂ N₆ ; Calculated: C, 65.20; H, 4.38; N, 30.42;Found: C, 65.34; H, 4.67; N, 30.50.

EXAMPLES 11-13

Employing conditions similar to those recorded in Example 10,7-H-pyrrolo[3,2-f]quinazoline-1,3-diamine, in dimethylformamide, isconverted to the sodium salt with ca. 50% sodium hydride-mineral oildispersion. The salt is treated with the indicated halide for the periodand at the temperature noted to provide the7-substituted-7H-pyrrolo[3,2-f]quinazoline-1,3-diamines described inTable II.

                                      TABLE II                                    __________________________________________________________________________    7-(Substituted)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamines                      ##STR3##                                                                                               Reax.                                                                             Reax.                                           Example                   Time                                                                              Time                                                                              Recryst.                                    No.    R.sup.1  Alkylating Agent                                                                        (°C.)                                                                      (hours)                                                                           Solv.                                                                              m.p., °C.                       __________________________________________________________________________    11   2-(4-methylpyridinyl)                                                                    2-fluoro-4-methyl-                                                                      135 4   methanol                                                                           263-264                                                pyridine                                                      12   4-trifluoromethyl-                                                                       p-fluorobenzotri-                                                                       110 6   methanol                                                                           272.5-273                                   phenyl     fluoride                                                      13   4-carbamoylphenyl                                                                        p-fluorobenzamide                                                                       110 5.5 DMSO/                                                                              333.5-334.5 (dec.)                                                       water                                       __________________________________________________________________________

EXAMPLE 14

The ability of the compounds of Formula I to inhibit the growth ofbacteria in vitro is demonstrated in the following test procedure:

A stock solution or suspension of the test compound at a concentrationof 2500 μg/ml. is prepared utilizing a suitable solvent or medium suchas aqueous sodium hydroxide, aqueous lactic acid, methyl cellosolve,dimethylsulfoxide, dimethylacetamide, ethylene glycol,dimethylformamide, formamide, propylene glycol, acetone or methanol.Two-fold dilutions are made by adding appropriate amounts of sterilewater to the solution or suspension of the test substance. One ml.quantities of each dilution are incorporated into Wellcotest SensitivityTest Agar fortified with 5% hemolyzed horse blood (9 ml. vol.) insterile Petri dishes to give plates containing varying concentrations ofthe test compound. The hardened surfaces of each plate are incubatedwith the test organism, and the plates are incubated for 18 hours at 35°C. The in vitro antibacterial activity of the compounds tested isexpressed as the "minimal inhibitory concentration" (MIC) which isdefined as the least amount of material (μg/ml.) that completelyinhibits the test organism.

The in vitro antibacterial activities of compounds of the invention areset forth in Tables III and IV below which set forth the MIC values ofvarious compounds when tested according to the above-describedprocedure:

                                      TABLE III                                   __________________________________________________________________________    In vitro Antibacterial Activity of 7-Substituted Methyl-7H-                   Pyrrolo[3,2-f]Quinazoline-1,3-Diamines                                         ##STR4##                                                                                      MIC (γ/ml.)                                                                     N.       S   K.                                      Compound         S.  S.  catar-                                                                             E.  para-                                                                             pneumo-                                                                           P.                                  of               aureus                                                                            aureus                                                                            rhalis                                                                             coli                                                                              typhi                                                                             niae                                                                              vulgaris                            Example                                                                               R        Smith                                                                             53-180                                                                            8193 9637                                                                              11737                                                                             10031                                                                             6896                                __________________________________________________________________________    2     2,4-dichlorophenyl                                                                       0.976                                                                             0.488                                                                             0.0038                                                                             3.9 31.3                                                                              0.488                                                                             --                                  3     3-acetylphenyl                                                                           0.122                                                                             0.061                                                                             --   0.244                                                                             0.976                                                                             0.031                                                                             3.9                                 4     3-carbomethoxyphenyl                                                                     0.976                                                                             0.122                                                                             --   1.95                                                                              31.3                                                                              0.244                                                                             125                                 5     3-isopropyloxyphenyl                                                                     1.95                                                                              0.488                                                                             3.9  7.81                                                                              31.3                                                                              0.244                                                                             62.5                                6     4-carboisopropyloxy-                                                                     0.488                                                                             0.488                                                                             0.122                                                                              15.6                                                                              62.5                                                                              0.488                                                                             125                                       phenyl                                                                  7     4-carbo-2-pentyloxy-                                                                     15.6                                                                              7.81                                                                              7.81 --  --  15.6                                                                              --                                        phenyl                                                                  8     4-carbomethoxyphenyl                                                                     31.3                                                                              7.81                                                                              --   62.5                                                                              250 15.6                                                                              250                                 9     4-hydroxyphenyl                                                                          0.488                                                                             0.488                                                                             --   0.976                                                                             3.90                                                                              0.244                                                                             250                                 __________________________________________________________________________

                                      TABLE IV                                    __________________________________________________________________________    In vitro Antibacterial Activity of 7-Substituted-7H-                          Pyrrolo[3,2-f]Quinazoline-1,3-Diamines                                         ##STR5##                                                                                      MIC (γ/ml.)                                                                     N.      S.  K.                                       Compound         S.  S.  catar-                                                                            E.  para                                                                              pneumo-                                                                           P.                                   of               aureus                                                                            aureus                                                                            rhalis                                                                            coli                                                                              typhi                                                                             niae                                                                              vulgaris                             Example                                                                               R.sup.1  Smith                                                                             53-180                                                                            8193                                                                              9637                                                                              11737                                                                             10031                                                                             6896                                 __________________________________________________________________________    10    4-pyridinyl                                                                              0.448                                                                             0.224                                                                             0.0152                                                                            0.244                                                                             0.976                                                                             0.976                                                                             62.5                                 11    2-(4-methylpyridinyl)                                                                    3.90                                                                              0.976                                                                             0.0152                                                                            3.9 7.81                                                                              0.244                                                                             15.6                                 12    4-trifluoromethyl-                                                                       31.3                                                                              31.3                                                                              --  250 --  3.9 --                                         phenyl                                                                  13    4-carbamoylphenyl                                                                        1.95                                                                              7.81                                                                              --  --  --  0.976                                                                             --                                   __________________________________________________________________________

EXAMPLE 15

The ability of compounds of this invention to demonstrate synergisticaction against anti-bacterial infections in mice when administered withsulfomethoxazole is demonstrated in the following test procedure:

The test agent is weighed, suspended in 0.5% aqueous carboxymethylcellulose, hemogenized (glass tissue grinder) and diluted according tothe design of the experiment. Mice (male, 18±1 g., CD-1 strain) arepre-weighed, pooled, infected at random intraperitoneally with a 0.5 ml.standardized suspension (LD₉₅ ±5%) of the bacterial organism in 5%gastric mucin and treated at random with single doses of the test agentseither at the time of infection or six hours after infecting. Thetreated groups consist of ten mice per dosage level. Deaths are recordeddaily for 14 days and the PD₅₀ (mice are treated at time of infection)and CD₅₀ (mice are treated six hours after infecting) values arecalculated by the method of Reed and Muench [Amer. J. Hyg., 27, (1938)].

                  TABLE V                                                         ______________________________________                                        In vivo Antibacterial Synergism Data (Mouse) for 7-                           (4-Pyridinyl)-7H-Pyrrolo[3,2-f]Quinazoline-1,3-Diamine                         ##STR6##                                                                      PD.sub.50.sup.a Values, mg. per kg., p.o.                                    Organism         Cpd.     SM.sup.b SM/Cpd.                                    ______________________________________                                        Escherichia coli (E-2)                                                                         >400     25       5.25/1.20                                  Escherichia coli (E-3)                                                                          312.8   28.1     12.5/6.25                                  Staphylococcus aureus CHP                                                                      >400     259.4       50/7.28                                 ______________________________________                                         .sup.a This value is the dose required to protect half of the mice from       death when the mice are treated immediately after infecting.                  .sup.b SM = sulfomethoxazole                                             

What is claimed is:
 1. A compound of the general formula: ##STR7## or anon-toxic acid addition salt thereof, wherein: Y is --CH₂ R or --R¹wherein: R is [2,4-dichlorophenyl, 3-acetylphenyl,]3-carbomethoxyphenyl, [3-isopropylphenyl,] 4-carbo-2-pentyloxyphenyl, or4-carbomethoxyphenyl;and R¹ is 4-pyridinyl or 2-(4-methylpyridinyl). 2.The compound as defined in claim 1 wherein R is 3-carbomethoxyphenyl. 3.The compound as defined in claim 1 wherein R is4-carboisopropyloxyphenyl.
 4. The compound as defined in claim 1 whereinR is 4-carbo-2-pentyloxyphenyl.
 5. The compound as defined in claim 1wherein R is 4-carbomethoxyphenyl.
 6. The compound as defined in claim 1wherein R¹ is 4-pyridinyl.
 7. The compound as defined in claim 1 whereinR¹ is 2-(4-methylpyridinyl).